The present invention, in some embodiments thereof, relates to environmentally-responsive compositions, and more particularly, but not exclusively, to compositions comprising a polymer-protein conjugate and an environmentally-responsive polymer, to scaffolds formed therefrom, and to uses thereof in, for example, tissue engineering.
Thermo-responsive polymers are capable of producing low viscosity aqueous solutions at low temperature, and forming a gel at a higher temperature, a property also referred to as “reverse thermal gelation”. These polymers are therefore also referred to as “reverse thermo-responsive” polymers. Thermo-responsive polymers have been widely used in biomedical applications, such as the development of injectable and controlled drug delivery systems [Qiu & Park, Adv Drug Deliv Rev 2001, 53:321-339]. In addition, thermo-responsive polymers have been used in the development of in situ generated implants [Cohn et al., Biomacromolecules 2005, 6:1168-1175] or plugs [Bouchot et al., Ann Thorac Surg 2010, 89:1912-1917].
U.S. Patent Application Publication No. 2011/0052490 describes a use of compositions comprising a purified thermo-responsive polymer in an endoscopic procedure for gastrointestinal mucosal resectioning.
Thermo-responsive polymers having a poly(ethylene oxide) (PEO)-poly(propylene oxide) (PPO)-PEO tri-block structure, referred to as “poloxamers”, have been reported to exhibit reverse thermal gelation. The endothermic sol-gel transition takes place due to an increase in entropy caused by release of water molecules bound to the PPO segments as temperature increases [Alexandridis, Colloid Surface A 1995, 96:1-46].
Pluronic® F127 poloxamer is a well known synthetic triblock copolymer (PEO99-PPO67-PEO99) [Nagarajan and Ganesh, J Colloid Interface Sci 1996, 184:489-499; Sharma and Bhatia, Int J Pharm 2004, 278:361-377; Cohn et al., Biomaterials 2003, 24:3707-3714], that exhibits a reverse thermal gelation (RTG) property above a critical temperature in aqueous solutions. Pluronic® F127 poloxamer is approved for use in humans by the U.S. FDA and has been investigated for biomedical applications such as drug carrier for a variety of routes of administration, artificial skin, and as a barrier for treating post operative adhesions [Escobar-Chavez, J Pharm Pharmaceut Sci 2006, 9:339-358].
Additional thermo-responsive polymers which exhibit reverse thermal gelation include commercially available poly(N-isopropylacrylamide) (PNIPAAm) and poly(N,N-diethylacrylamide) (PDEAAm).
International Patent Application PCT/IL2004/001136 (published as WO 2005/061018) and U.S. Pat. No. 7,842,667 disclose polymer-protein conjugates such as PEG (polyethylene glycol)-fibrinogen conjugates, and biodegradable scaffolds generated by cross-linking the conjugates, for example, by UV light. The scaffolds may be used for treating disorders requiring tissue regeneration.
PEG-fibrinogen hydrogels mimic the extracellular matrix (ECM), and contains necessary cell signaling domains within its amino acid sequence, including adhesion and protease degradation substrates, while the structural properties of the biosynthetic hydrogel network are controlled through the synthetic component [Dikovsky et al., Biomaterials 2006, 27:1496-1506].
International Patent Application PCT/IL2010/001072 (published as WO 2011/073991) discloses polymer-protein conjugates comprising a protein attached to at least two polymeric moieties, at least one of which exhibits reverse thermal gelation. The conjugates are suitable for being cross-linked by non-covalent and/or covalent cross-linking. The conjugates and compositions-of-matter formed by cross-linking the conjugates may be used for cell growth, tissue formation, and treatment of disorders characterized by tissue damage or loss.
Additional art includes Cohn et al. [Polym Adv Tech 2007; 18:731-736].